The total synthesis of several representative biologically active macrocyclic natural products in the cembrane and pseudopterane family will be undertaken in order to develop reliable methodology for the preparation of such compounds and analogues thereof. There are three major considerations in this research project: (1) the synthesis of enantioenriched acyclic precursors in high ee by stereochemically rational routes; (2) cyclization of such precursors leading to macrocyclic intermediates of well-defined stereochemistry; (3) further manipulations of these macrocyles by stereo and regioselective transformations to the desired natural products of analogues. The first consideration encompasses an area of intense current research interest. Several of the evolving new methods should be applicable to the required precursors. Work on the formation of macrocarbocyclic rings and their selective chemical transformations, on the other hand, is still at an early stage of development. We expect conformational analysis through computer assisted molecular modeling to play a major role in evaluating possible reaction pathways. The target compounds and their analogues show promise of important biological activity in the inhibition of tumor promotion, as antiinflammatory agents, and as neurotoxins. Compounds prepared in these studies will be made available to NIH for biological evaluation through Starks C.P. Additional testing at other academic institutions is also envisioned.